I. Field of Invention
The present invention provides a new method for treating pulmonary distress caused by low or insufficient surfactant production in infants, children or adults. More particularly, the method of the invention utilizes leptin to treat individuals with impaired lung surfactant production and is particularly useful for treating Respiratory Distress Syndrome (RDS) in premature infants.
II. Backgroud of Invention
Premature infants are at increased risk for developing Respiratory Distress Syndrome (RDS), the leading cause of neonatal morbidity and mortality in developed countries (Mendelson et al., Bailliere's Clin. Endocrinol. Metab. 4:351-78, 1990). This condition is caused by a deficiency of lung surfactant, a complex material consisting of phospholipids, neutral lipids, carbohydrate and proteins. These infants require assisted ventilation and supplemental oxygen for prolonged periods of time. Often these infants develop Bronchopulmonary Dysplasia (BPD), a chronic lung disease associated with neurodevelopmental delay, poor growth, and late mortality (Bader et al., J. Pediatr. 110(5):693-9, 1987; Gibson et al., Am. J. Dis. Child. 143(7):721-5, 1988; Kurzner et al., Pediatrics 81(3):379-84, 1988; Vohr et al., Dev. Med. Child. Neurol. 33(8):690-7, 1991). Inflammation, primarily due to oxygen-induced free radical formation, positive pressure ventilation, and infection, is thought to be a key factor in the lung injury observed in these infants (Pierce and Bancalari, Pediatr. Pulmonol. 19(6):371-8, 1995).
Strategies aimed at treating the pulmonary inflammation in BPD through the use of systemic steroids have not shown a favorable outcome in decreasing the overall incidence of this disease. Three large multicenter trials, which enrolled a total of 1348 infants, independently showed no significant benefit to early administration (within 72 hours of life) of steroids on the incidence of BPD (Halliday et al., In: Hot Topics in Neonatology, Ross Laboratories, pp. 267-75, 1999; Soll et al., Pediatr. Res. 45: 226A, 1999; Stark et al., Pediatrics Supplement 104: 739A, 1999). Two of these trials were stopped prematurely due to concerns of significant detrimental side effects, including gastrointestinal perforation, periventricular leukomalacia, poor weight gain, gastrointestinal hemorrhage, and hypertension. Long term follow-up studies have shown a significant detrimental effect on somatic growth (Gibson et al., Arch. Dis. Child 69: 505-9, 1993, Yeh et al., Pediatrics 101(5):E7, 1998; O'Shea et al., Pediatrics 104(1 part 1):15-21, 1999). These adverse effects may be related to the catabolic effects of steroids on growing tissues (Tsai et al., Act. Paediatr. 85(12):1487-90, 1996). Efforts to reduce the incidence of BPD using other strategies such as inhaled steroids, high-frequency ventilation, and treatment of RDS with surfactant have also shown mixed results. There has been some success in reducing the incidence of RDS by enhancing surfactant production in utero via glucocorticoid administration to mothers in preterm labor (Liggins and Howie, Pediatrics 59:515-25, 1972). However, this treatment strategy is dependent on accurate identification of those mothers at risk for preterm delivery, and thus, is only effective for a small subset of premature infants affected with RDS. Furthermore, despite significant advances in neonatal care during the past three decades, the incidence of RDS and BPD has not changed significantly. There remains a clear need to identify alternative treatment strategies for this disease.
As more fully described below, the present invention overcomes the problems associated with previous forms of RDS therapy and includes a novel method of treating RDS that can be administered to premature infants as well as infants, children or adult subjects who have deficient lung surfactant.